A large global study provides evidence that risk-reducing mastectomy (RRM) and/or risk-reducing salpingo-oophorectomy (RRSO) is associated with improved survival outcomes in young women diagnosed with breast cancer (BC) at or before 40 years of age who were harbouring germline BRCA1 and/or BRCA2 pathogenic variants (PVs).

“Cancer risk management strategies, including RRM and RRSO, are widely recommended in BRCA healthy carriers,” said Dr Matteo Lambertini from the University of Genova in Italy, at SABCS 2024. “However, in BRCA carriers with a history of BC, additional challenges [eg, impact on fertility and quality of life] should be carefully considered in counselling regarding RR surgeries, especially among young patients.”

Evidence focusing on the role of RRM and/or RRSO in BRCA carriers with a history of BC at a young age (ie, ≤40 years at diagnosis) is lacking. Hence, the team leveraged data from the retrospective BRCA BCY Collaboration study that evaluated patients with stage I?III invasive BC diagnosed at ≤40 years who had germline likely pathogenic or PVs of BRCA.

A total of 5,290 patients were included in the analysis. Median age at diagnosis was 35 years. About two-thirds (63.5 percent) of participants were BRCA1 carriers, 51.2 percent had node-negative disease, and nearly 50 percent had triple-negative BC (TNBC).

Fifty-five percent (n=2,910) underwent RRM, while 52.6 percent (n=2,782) underwent RRSO. A total of 1,804 patients opted for both surgeries. [SABCS 2024, abstract GS1-08]

After a median follow-up of 5.1 years after RRM, those who underwent RRM had significantly better OS than those who did not (adjusted hazard ratio [aHR], 0.65). The favourable impact of RRM on OS was observed regardless of specific BRCA gene, age at diagnosis, tumour subtype, tumour size, nodal status, chemotherapy use, timing of BRCA testing, and income (aHRs ranging between 0.54 and 0.90).

Likewise, RRSO was associated with a significant OS improvement (aHR, 0.58) after a median follow-up of 4.9 years after RRSO. The OS benefit varied by BRCA gene and tumour subtype, with greater reductions in the risk of death among those with germline BRCA1 vs BRCA2 mutation (aHRs, 0.44 vs 0.85; p_interaction=0.001) and those with TNBC vs hormone receptor-positive BC (aHRs, 0.44 vs 0.80; p_interaction=0.009).

Lambertini attributed the greater OS benefit among BRCA1 carriersto the lower risk of ovarian cancer in BRCA2 carriers, the very young age of study participants, and the relatively short follow-up. The greater OS benefit among those with TNBC may have been driven by the different distribution of BC subtypes in BRCA1 vs BRCA2 carriers, he added.

The risk of disease-free survival (DFS) events also dropped with RRM and RRSO (aHRs, 0.58 and 0.68, respectively), as did the risk of BC-free interval events (BCFI; aHRs, 0.55 and 0.65).

RRM and RRSO subgroup

Among those who underwent both RRM and RRSO, no significant interaction was seen between RRM and RRSO on OS (p_interaction=0.829). According to Lambertini, this suggests that the effect of either approach was independent. Conversely, the effect of RRSO was more pronounced among those who also underwent RRM, as reflected by the significant interaction in DFS (p_interaction=0.054) and BCFI (p_interaction=0.006).

“When interpreting these results, we should keep in mind that this is a young patient population with a high risk of developing a second primary BC, which counts as an event for the DFS and BCFI definitions,” noted Lambertini.

May improve counselling on risk management strategies

“[Taken together,] our results showed that undergoing RRM and RRSO was associated with improved OS, DFS, and BCFI in this special clinical setting,” Lambertini said.

“The findings may help improve counselling on cancer risk management strategies for BRCA carriers with young-onset BC,” he continued. However, Lambertini underlined that the results should not be used for counselling BRCA healthy carriers or BRCA carriers with a BC diagnosis at an older age.